Recent progress in the development of new cytotoxic drugs and improved treatment protocols have made chemotherapy successful in the treatment of various types of human cancers. However, there are important limitations to this method of treatment. For example, the chemotherapeutic agents exhibit both acute and cumulative toxicity for normal (i.e., noncancerous) tissues such as the heart, kidneys and bone marrow. The development of more selective therapeutic drugs and improved methods of delivery should help alleviate this problem. An equally significant limitation to the use of chemotherapy is the emergence and outgrowth of drug resistant cells. This problem is a particularly difficult one because tumor cells often become resistant to a broad spectrum of structurally and functionally unrelated drugs to which they have not been previously exposed. It is unlikely that this problem will be solved by the development of new drugs using presently available methods, however, because such cells are likely to exhibit crossresistance to these new agents. This phenomenon of resistance to multiple drugs has been termed multidrug resistance.
The basis for the development of resistance to a broad spectrum of drugs by cells is inherently difficult to study in vivo because of the heterogenous nature of the cell populations present in tumor specimens. In vitro models have been developed to study this phenomenom. Cultured rodent and human cells highly resistant to multiple cytotoxic drugs have been obtained by cultivating these cells in increasing concentrations of a single drug. Such cell lines have proven very useful in the study of the molecular parameters underlying multidrug resistance. For example, multidrug resistant cells (i.e., cells which exhibit resistance to a broad spectrum of drugs) have been shown to contain double minute chromosomes or homogeneously staining chromosomal regions, which suggests gene amplification contributes to multidrug resistance. Specifically, adriamycin- and colchicine-resistant hamster cells have been shown to contain amplified DNA fragments, some of which are amplified in both types of cells. A small segment of one of these commonly amplified fragments has been cloned by Roninson and co-workers and its degree of amplification has been shown to correlate with the degree of drug resistance. Roninson, I. B. et al., Nature, 309: 626-629. It has been suggested that decreased intracellular drug accumulation resulting from alterations in the plasma membrane is the mechanism by which multidrug resistance occurs. Ling, V. et al.: Cancer Treatment Report, 67:869-875 (1983); Inaba, M. et al.: Cancer Research, 39:2200-2206 (1979); Ling, V. and L.H. Thompson: Journal of Cell Physiology, 83:103-111 (1974). It has also been postulated that a plasma membrane glycoprotein of relative molecular mass 170,000 (designated P-glycoprotein), consistently found in multidrug resistant cell lines and transplantable tumors, in some way mediates multidrug resistance. Riordan, J.R. et al.: Nature, 316:817-819 (1985). In spite of considerable interest in and study of multidrug resistance, however, its basis remains unknown.